Overuse, incorrect use and agricultural use of antibiotics has led to the emergence of resistant bacteria that are refractory to eradication by conventional anti-infective agents, such as those based on carbapenem, cephalosporin or fluoroquinolone architectures. Alarmingly, many of these resistant bacteria are responsible for common infections including, for example, pneumonia, sepsis, etc.
The dearth of new antibiotic agents, which, inter alia, is due to termination of research and development efforts to develop new antibiotics agents, has exacerbated the above situation. Even at this date, when a clear need for novel antibiotic agents has been established, reduced economic incentives and heightened regulatory requirements has prevented substantial investment by pharmaceutical organizations in this increasingly critical issue in health care.
Failure to provide new agents to treat resistant bacteria threatens the many benefits achieved with antibiotics in the recent past. Accordingly, what is need are novel antibiotic compounds which are effective against resistant bacteria and are simple to manufacture and use.
The present application satisfies these and other needs by providing deuterated O-sulfated beta-lactam hydroxamic acids and deuterated N-sulfated beta-lactams, which may be used to treat infectious diseases. In one aspect, tigemonam or aztreonam, where any or up to all of the non-exchangeable hydrogen atoms are substituted with deuterium are provided.
In another aspect, a compound of structural Formula (I) is provided:
and pharmaceutically acceptable salts, hydrates and solvates thereof, where R1 and R2 are independently hydrogen, deuterium, —CH3, —CD3, —CD2H or —CDH2, R3 is hydrogen or deuterium, R4 is —SO3H or —OSO3H, R5 is heteroaryl or substituted heteroaryl optionally substituted with one or more deuterium atoms; and R6 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or —CO2H, optionally substituted with one or more deuterium atoms, provided that at least one non-exchangeable hydrogen atom is substituted with deuterium.
Also provided are derivatives, including esters, enol ethers, enol esters, metabolites and prodrugs of the compounds described herein. Further provided are pharmaceutical compositions which include the compounds provided herein and a pharmaceutically acceptable vehicle.
Methods of treating, preventing, or ameliorating symptoms of infectious disease in a subject are also presented herein. The methods generally involve administering a therapeutically effective amount of deuterated O-sulfated beta-lactam hydroxamic acids and/or deuterated N-sulfated beta-lactams, or pharmaceutical compositions thereof to the subject.